Central AT1 receptors and the integrated stress response.

中枢 AT1 受体和综合应激反应。

• 批准号: 7707282
• 负责人: Eric Gerald Krause
• 金额: $ 12.26万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707282
• 关键词: Acute; Address; Adrenal Glands; Affect; Affective; American; Angiotensin II; Angiotensins; Anxiety; Anxiety Disorders; Base of the Brain; Behavior; Behavioral; Binding; Biological; Blood; Blood Pressure; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Chronic; Chronic stress; Clinical Research; Computer Systems Development; Corticosterone; Corticotropin-Releasing Hormone; Disease; Disease Progression; Endocrine; Exposure to; Functional disorder; Heart Rate; Hormones; Hypertension; Hypothalamic structure; Laboratory Rat; Measures; Mediating; Mediation; Mediator of activation protein; Mental Health; Mental disorders; Mood Disorders; Neuroanatomy; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peptides; Phase; Pituitary Gland; Prosencephalon; Rattus; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reporting; Research Design; Risk; Role; Severities; Stimulus; Stress; Structure; Subfamily lentivirinae; Subfornical Organ; System; Testing; Thymus Gland; Up-Regulation; Weight; acute stress; biological adaptation to stress; brain tissue; cardiovascular disorder risk; clinical application; feeding; heart rate variability; hypothalamic-pituitary-adrenal axis; improved; indexing; paraventricular nucleus; pressure; receptor; receptor expression; research study; response

DESCRIPTION (provided by applicant): Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate, that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascular disease. While the onset of hypertension is attributed to over activity of the renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide of the RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (ATI R). Interestingly, ATI R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. In this regard, our recent study found that circulating ANGII drives activation of the HPA axis by stimulating AT1R in the subfornical, a specialized forebrain structure that binds blood-borne hormones. Because repeated stress increases ATI R expression in the subfornical organ, it is likely that chronic stress potentiates the influence of circulating ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-based disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will utilize antisense oligodeoxynucleotides to inhibit AT1R expression in the subfornical organ of laboratory rats to determine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to acute and chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the subfornical organ will limit stress responding and alleviate the deleterious consequences of chronic stress exposure.

描述（由申请人提供）：高血压影响约5000万美国人，这种疾病的进展显着增加了心血管疾病的风险。最近的临床研究表明，高血压也与心理健康障碍有关。具体而言，高血压会增加焦虑症的风险，而焦虑症则可以预测高血压和心血管疾病的风险和严重程度。虽然高血压的发作归因于肾素 - 血管紧张素系统（RAS）的过度活性，但焦虑的发展与下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴的失调有关。 Ras的效应肽，血管紧张素II（Angii）通过激活血管紧张素1型受体（ATI R）发挥其大部分生物学作用。有趣的是，在整个HPA轴上都表达了ATI R，而新兴的证据则暗示了Angii是压力反应的重要中介。长期暴露于压力的情况下调了HPA轴和RAS，从而对心血管和心理健康产生负面影响。鉴于慢性应激类似地上调了HPA轴和RA，因此这些系统之间的相互作用很可能是慢性应激对心理健康和心血管功能的影响的基础。在这方面，我们最近的研究发现，循环的Angii通过在结合血源激素的专门的前脑结构中刺激AT1R来驱动HPA轴的激活。由于反复的应力增加了亚饰有器官中ATI R的表达，因此慢性应激可能增强了循环ANGII对HPA轴的影响，从而诱导心血管和情感障碍。总的来说，这些研究表明，针对RAS的疗法可能会影响诸如焦虑之类的脑部疾病的开始，因此，了解影响压力反应的中心血管紧力途径很重要。因此，所提出的实验将利用反义寡脱氧核苷酸来抑制实验室大鼠亚染色器官中的AT1R表达，以确定这些受体对心血管，HPA的贡献，以及对急性和慢性暴露于应激的心血管响应以及行为反应。这些研究旨在检验总体假设，即抑制AT1R在亚官方器官中会限制应力反应并减轻慢性应激暴露的有害后果。